WO2006100602A2

WO2006100602A2 - Immediate release stable solid oral dosage forms op fosinopril

Info

Publication number: WO2006100602A2
Application number: PCT/IB2006/000922
Authority: WO
Inventors: Amol Kulkarni; Vijender Gupta; Maheswaran Vasudevan; Ashish Gogia; Sivakumaran Meenakshisunderam; Jagadeesh Thipperudraiah; Vinod Joseph
Original assignee: Aurobindo Pharma Ltd
Current assignee: Aurobindo Pharma Ltd
Priority date: 2005-03-22
Filing date: 2006-03-20
Publication date: 2006-09-28
Anticipated expiration: 2007-09-22
Also published as: WO2006100602A3

Abstract

The present invention relates to stable solid oral dosage forms of fosinopril or its acceptable salts. More particularly, the present invention relates to stable solid oral dosage forms where the lubricant is selected from glyceryl palmitostearate, sodium lauryl sulfate, silicon dioxide, polaxomer or a combination thereof.

Description

IMMEDIATE RELEASE STABLE SOLID ORAL DOSAGE FORMS OF AN ANTIHYPERTENSIVE DRUG

Field of the invention The present invention relates to stable solid oral dosage forms of an antihypertensive drug. More particularly, the present invention relates to stable solid oral dosage forms of fosinopril or its pharmaceutically acceptable salts.

The present invention also relates to stable solid oral dosage forms of fosinopril or its pharmaceutically acceptable salts in combination with diuretics. The present invention also relates to a process for the preparation of stable solid oral dosage forms of fosinopril or its pharmaceutically acceptable salts.

Background of the invention

Fosinopril is the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, fosinoprilat. Fosinopril is L-proline, trans- 4-cyclohexyl-l-[[[2-methyl-l- (l-oxopropoxy)propoxyl](4-phenylbutyl)phosphinyl] acetyl] sodium salt, disclosed and claimed in US Patent No. 4,337,201. Fosinopril alone or in combination with a diuretic, particularly a thiazide diuretic is indicated for the treatment of hypertension. It is also used as an adjunctive therapy for the management of heart failure as part of a conventional therapy that includes diuretics and, optionally, digitalis. Fosinopril is commercially marketed as Fosinopril sodium under the trade name MONOPRIL^®.

Fosinopril sodium has a relatively low bulk density, exhibits poor flow characteristics, and adheres to metal surfaces during tableting. Thakur et. al (Pharm. Res. 10 (6) 800-809 (1993)) suggested that the degradation of fosinopril in magnesium stearate compositions is due to the effect of the Mg metal ion, which: is further enhanced by relative humidity. They also discussed the relative reactivities of different metal ions on fosinopril. These features of fosinopril make the manufacturing of tablets highly problematic and hence, there is need- for careful selection and incorporation of excipients. There are few patents/patent publications, which disclose the tablet formulations of fosinopril sodium by selecting the lubricants other than magnesium stearate. Given below are the patents/ publications which describes the compositions of fosinopril: US patent No. 5,006,344 discloses that tablets with improved stability can be obtained by eliminating magnesium stearate and using either sodium stearyl fumarate or hydrogenated vegetable oil as the lubricant.

US 2005/0202083 discloses composition of fosinopril tablet comprising fosinopril and a combination of colloidal silicon dioxide and talc. US 2005/0256086 discloses composition of fosinopril, comprising glyceryl dibehenate as a lubricant.

US 2005/0095287 discloses pharmaceutical tablet formulation which comprises a pharmaceutically effective amount of fosinopril sodium and a lubricant wherein the lubricant is selected from the group consisting of sodium stearate and a mixture composed of stearic acid esters, propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate, and silicon dioxide.

US 2002/0131999 discloses tablet composition of fosinopril sodium containing stearic acid and zinc stearate as lubricant. This patent publication further discloses the degradation products on percentage of the initial fosinopril sodium. It appears from the above patents /publications, that the qualitative and quantitative selection of excipients is critical to avoid the possible degradation of solid dosage forms of fosinopril sodium mediated by magnesium (metal ion) and hydrolysis. However, we found that stable solid oral dosage forms of fosinopril may be made either by the addition of suitable stabilizers along with metal ion lubricant or by selecting metal ion free excipients exhibiting excellent lubricant properties. , During continuous efforts to develop stable solid dosage forms of fosinopril to avoid possible degradation, inventors of the present invention found that shelf life and stability of fosinopril sodium can be increased by using glyceryl palmitostearate, sodium lauryl sulfate, polaxomer or combination thereof with or without auxiliary stabilizer.

Objective of the invention

Accordingly, the main objective of present invention is to provide stable solid dosage forms of fosinopril, which minimize the degradation of fosinopril sodium and maintains the potency during the storage.

Another objective of the present invention is to provide stable solid dosage forms of fosinopril in such a way that it will comply with the reference product in terms of in vitro parameters like dissolution, disintegration etc and in vivo parameters like bioequivalence.

Yet another objective of the present invention is to provide simple, and efficient process for preparing stable solid dosage forms of fosinopril on a commercial scale.

Siimmary of the invention According to the main embodiment of the present invention, there is provided stable solid dosage forms comprising fosinopril or its pharmaceutically acceptable salts and a lubricant selected from the group consisting glyceryl palmitostearate, sodium lauryl sulfate, silicon dioxide, polaxomer or combination thereof. Detailed description of the invention

In an embodiment of the present invention, the stable solid dosage forms of fosinopril further comprises diuretics.

Suitable diuretics according to the present invention include furosernide, spironolactone, chlorthalidone, amiloride, triamterene, and thiazide diuretics such as hydrochlorothiazide, chlorothiazide, flumethiazide, and bendroflumethiazide.

The stable solid dosage forms of fosinopril further comprise one or more pharmaceutically acceptable excipients such as diluents, disintegrants, binders and the like. In an embodiment of the present invention, the pharmaceutically acceptable salts of fosinopril include sodium, potassium, calcium and the like.

In an embodiment of the present invention, the solid dosage form may optionally contain stabilizer. The use of suitable class of stabilizer in combination with lubricants produces stable solid dosage forms by minimizing the degradation of fosinopril. Suitable classes of stabilizers of the present invention are selected from antioxidants, chelating agent and moisture scavengers.

Suitable antioxidants of the present invention are selected from true antioxidants such as butylated hydroxy toluene (BHT), butylated hydroxy anisole, (BHA), cysteine hydrochloride and the like; reducing agents such as ascorbic acid, sodium bisulphate, sodium metabisulphite, sodium sulphate and the like.

Suitable chelating agents such as edetic acid (EDTA), diethyltriaminepetaacetic acid (DTPA), hyroxyethylenediaminetriacetic acid (HEDTA), Nitrilotriacetic acid (NTA), and their salts and the like. Suitable moisture scavengers can be either edible which is part of formulation recipe such as moisture barrier films for example polyvinyl alcohol, ethyl cellulose, methacrylic acid polymer, opagloss, opadry AMB, shellac, as well as desiccants for example syloid, colloidal silicon dioxide or non-edible moisture scavengers such as packaging material (container and components required for packaging) for example silica gel, molecular sieves or combination thereof. The possible degradation of fosinopril tablets by moisture may be reduced by coating the tablets with moisture barrier coating using polyvinyl alcohol, ethyl cellulose, methacrylic acid polymers and the like and packing these tablets along with^, sjlica gel or molecular sieves. Coating the fosinopril tablets with these materials prevent the entry of moisture into the tablets of fosinopril and silica gel or molecular sieves further absorbs moisture traces and thus makes the tablets stable during storage.

In yet another embodiment of the present invention, the stable tablet dosage forms of fosinopril or its pharmaceutically acceptable salts further comprises one or more pharmaceutically acceptable excipients selected from diluents such as cellulose-microcrystalline, cellulose powdered, polyols such as mannitol, sorbitol, xylitol, maltitol, sucrose, lactose, dextrates, dextrins, fructose, kaolin, starch, pregelatinsed starch, compressible sugar and combinations thereof; disintegrants such as pregelatinised starch, crosscarmellose sodium, crosspovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, starch, carboxymethyl cellulose, and the like or combination thereof; binders such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylates, carbomers, xanthan gum, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, plasdone and the like.

In yet another embodiment of the present invention, the solid dosage form may be tablets, capsules, powder for reconstitution, sachets, bilayer tablets and the like. The different formulation processes that can be employed for manufacturing the disclosed formulations are wet granulation using aqueous or non aqueous solvents, direct compression and compaction granulation techniques.

Fosinopril tablets prepared by any of the above methods may optionally be coated with one or more functional and /or non-functional coatings, if desired. The invention is further exemplified with following examples and is not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. ^" Example 1 Fosinopril Sodium + Hydrochlorothiazide Tablets 20/12.5 mg

The processing steps that were involved in making fosinopril sodium + hydrochlorothiazide tablets are as given below: i) sifted and mixed fosinopril sodium, hydrochlorothiazide, lactose, part of croscarmellose sodium and iron oxide, ii) dissolved povidone in IPA and granulated the materials of step (i), iii) dried and sifted the granules of step (ii), iv) lubricated the blend obtained in step (iii) with remaining croscarmellose, sodium, silicon dioxide, glyceryl palmito stearate & sodium lauryl sulfate, and v) compressed the lubricated blend in to tablets or filled in to capsules.

Example 2 Fosinopril Tablets

The processing steps that were involved in making fosinopril tablets are as given below: i) sifted and mixed fosinopril sodium, lactose, part of microcrystalline cellulose and part of crospovione, ii) dissolved povidone in IPA and granulated the materials of step (i), iii) dried and sifted the granules of step (ii), iv) lubricated the blend obtained in step (iii) with remaining microcrystalline cellulose, remaining crospovidone, silicon dioxide and polaxamer, and v) compressed the lubricated blend in to tablets or filled in to capsules.

Stability Data: Tablets of example 1 were stored at 40 ⁰C/ 75% RH, for .two months and then tested by an HPLC method to determine the fosinopril sodium related compound A as a percentage of the initial fosinopril sodium content. The data is given in table 1.

Table 1

Claims

Claims:

1. A stable solid dosage form comprising fosinopril or its pharmaceutically acceptable salts and a lubricant selected from the group consisting of glyceryl palmitostearate, sodium lauryl sulfate, silicon dioxide, polaxomer or combination thereof.

2. The dosage form as claimed in claims 1, further comprises a diuretic.

3. The dosage form as claimed in claim 2, wherein the diuretic is furosemide, spironolactone, chlorthalidone, amiloride, triamterene, hydrochlorothiazide, chlorothiazide, flumethiazide or bendroflumethiazide.

4. The dosage form as claimed in claims 1 to 3, further comprise one or more pharmaceutically acceptable excipients such as diluents, disintegrants and binders.

5. The dosage form as claimed in claim 4, wherein diluent is selected from cellulose-microcrystalline, cellulose powdered, polyols such as mannitol, sorbitol, xylitol, maltitol, sucrose, lactose, dextrates, dextrins, fructose, kaolin, starch, pregelatinsed starch, compressible sugar and combinations thereof.

6. The dosage form as claimed in claim 4, wherein disintegrant is selected from pregelatinised starch, crosscarmellose sodium, crosspovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, starch, carboxymethyl cellulose, or combination thereof.

7. The dosage form as claimed in claim 4, wherein binder is selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylates, carbomers, xanthan gum, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, plasdone.

8. ^"The dosage form as claimed in claims 1 to 7, in the form of tablets, capsules, powder for reconstitution, sachets, or bilayer tablets.

9. The dosage form as claimed in claim 1, further comprises a stabilizer selected from the group consisting of chelating agent, antioxidant or moisture scavenger.

10. The solid dosage form as claimed in claim 9, wherein the chelating agent is selected from edetic acid (EDTA), diethyltriaminepetaacetic acid (DTPA), hyroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), and their salts. -A

1 1. The solid dosage form as claimed in claim 9, wherein the antioxidant is selected from butylated hydroxy toluene (BHT), butylated hydroxy anisole, (BHA), cysteine hydrochloride, ascorbic acid, sodium bisulphate, sodium metabisulphite or sodium sulphate.